Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. CLL results in profound immune suppression, and infection is a leading cause of mortality in CLL patients. Unfortunately, many current frontline therapies exacerbate this immune suppression. There is an urgent need for treatment that will target the tumor but also sustain or enhance the patient's immune response. Interleukin-21 (IL-21), a cytokine that has immune regulatory effects, presents an exciting potential therapy because it has immune stimulating properties but can also directly kill the CLL tumor cells. Our lab has shown that response to IL-21 directly correlates with the expression of the IL-21 receptor (IL-21R), which varies between patients. In order to improve patient response and design rational combination therapies with IL-21, we propose to elucidate the regulation of IL-21R in malignant B cells. This will be accomplished through the use of two clinically relevant immunomodulatory compounds. Our aims are 1) to determine the mechanism by which these compounds upregulate IL-21R in CLL cells and 2) to interrogate the role of IL-21 and its receptor in the immunomodulatory effects of these compounds. Experiments to assess gene regulation, protein induction, and cytotoxicity will be performed in primary patient cells and whole blood as well as in the Tcl1 mouse model of CLL. Our long-term goal is to improve CLL therapy by enhancing IL-21's anti-tumor and immune stimulating effects through combinations with other clinically relevant treatments.